Supplementary Appendix

Transkript

1 Supplementary Appendix This appendix has been provided by the authors to give readers additional information about their work. Supplement to: Schüpke S, Neumann F-J, Menichelli M, et al. Ticagrelor or prasugrel in patients with acute coronary syndromes. N Engl J Med 2019;381: DOI: /NEJMoa

2 Supplementary Appendix PROSPECTIVE, RANDOMIZED TRIAL OF TICAGRELOR VERSUS PRASUGREL IN PATIENTS WITH ACUTE CORONARY SYNDROMES INTRACORONARY STENTING AND ANTITHROMBOTIC REGIMEN: RAPID EARLY ACTION FOR CORONARY TREATMENT ISAR- REACT 5 Protocol GE-IDE-No EudraCT-No This supplement contains the following items: 1. Investigators and Committees Coordinating ISAResearch Center Figures Figure S1. One-Year Incidences and Hazard Ratios of the Primary End Point of Death, Myocardial Infarction, or Stroke in Pre-specified Subgroups Tables Table S1. Angiographic Characteristics 14 Table S2. Procedural Characteristics 15 Table S3. Diagnosis and Drug Therapy at Discharge 17 Table S4. Antithrombotic Medication After Discontinuation of Study Drug During Follow-up 18 Table S5. Base-Line Characteristics of Patients with Incomplete vs Complete One-Year Follow-up Inclusion and Exclusion Criteria End point definitions References Page 1 / 33

3 1. Investigators and Committees Country: Germany Deutsches Herzzentrum München, Munich Katharina Mayer (PI, AUG/2015), Stefanie Schüpke (Schulz) (PI, SEP/2013-AUG/2015), Raphaela Hilz (Lohaus) (Sub-PI, AUG/2015), Katharina Mayer (Sub-PI, SEP/2013- AUG/2015) Investigators: Stephanie Ast, Sara Ates, Anja Batrice, Janika Bohner (Repp), Felix Bourier, Christof Burgdorf, Robert Byrne, Salvatore Cassese, Antoinette de Waha, Julia Ellert, Massimiliano Fusaro, Senta Gewalt, Christian Grebmer, Philipp Groha, Friederike Gusmini (Gauwerky), Christian Hengstenberg, Katrin Huber, Oliver Husser, Henning Jansen, Johannes Jehle, Michael Karl, Adnan Kastrati, Thorsten Kessler, Martin Klügl, Katharina Koch- Büttner, Marielouise Kornmayer, Marc Kottmaier, Sebastian Kufner, Vivien Kujath, Constantin Kuna, Anna Lena Lahmann, Clarissa Lanig, Carsten Lennerz, Elke Lorenz, Amadea Erben (Martischnig), Tanja Morath, Jonathan Nadjiri, Suzan Nasifoglu, Philipp Nicol, Ilka Ott, Costanza Pellegrini, Vanessa Pfetsch, Tilko Reents, Tobias Rheude, Stefanie Rosner, Elena Risse (Rousseva), Dennis Rubach, Philipp Moritz Rumpf, Veronika Sanin, Dominique Sauter, Anna-Katharina Schmidt, Raphael Schmieder, Friederike Schürmann, Verena Kantenwein (Semmler), Iva Simunovic, Carolin Sonne, Susanne Tholen, Kerstin Trappe, Teresa Trenkwalder, Felix Voll, Moritz von Scheidt, Severin Weigand, Simon Wernhart, Jens Wiebe, Fritz Wimbauer, Janina Winogradow, Isabel Wustrow, Erion Xhepa Study Nurses: Bettina Harrer, Kerstin Maisburger, Daniela Schemmer Department of Cardiology and Angiology II, University Heart Center Freiburg Bad Krozingen Franz-Josef Neumann (PI), Dietmar Trenk (Sub-PI) Investigators: Michael Amann, Torqa Aurel, Johannes Bremicker, Heinz-Joachim Büttner, Marco Cederqvist, Christian Claus, David De Pasquale, Felix Gaiser, Samuel Hemmerling, Willibald Hochholzer, Julia Hromek, Stefan Leggewie, Matthias Lippert, Nikolaus Löffelhardt, Sebastian Merz, Björn Müller-Edenborn, Thomas Nührenberg, Florian Riede, Roland Schmitz, Undine Schulz, Christian Stratz, Jochen Strübin, Christian Valina, Vera von Kapherr, Valentin Wennekes-Neagu, Markus Zwigart Study Nurses: Erik de Frenne, Cornelia Ebel, Christina Gaus, Christina Lange, Daniela Reichenbach Page 2 / 33

4 Medizinische Klinik und Poliklinik Innere Medizin I (Kardiologie, Angiologie, Pneumologie), Klinikum rechts der Isar, Munich Karl-Ludwig Laugwitz (PI), Isabell Bernlochner (Sub-PI, SEP/2013), Rainer Okrojek (Sub- PI, NOV/2016) Investigators: Wala Al Rabia, Anja Batrice, Anna Berkefeld, Janika Bohner (Repp), Dario Bongiovanni, Felix Bourier, Christian Bradaric, Eva-Maria Brandner (Steinlecher), Alessandra Buiatti, Ralf Dirschinger, Michael Dommasch, Marijana Dzijan-Horn, Katharina Engel, Verena Freiberger, Constantinos Gatos, Alexander Goedel, Frederik Götte, Christian Grebmer, Philipp Groha, Sebastian Herberger, Peter Herhaus, Petra Hoppmann, Tareq Ibrahim, Juliane Jaitner, Michael Karl, Irina Kerle, Thorsten Kessler, Tobias Koppara, Hans Kossmann, Kristin Kuhs, Anna Lena Lahmann, Nicolas Langwieser, Elke Lorenz, Arne Müller, Tobias Rheude, Kristina Riedmann, Elena Risse (Rousseva), Stefanie Rosner, Michael Rühl, Philipp Moritz Rumpf, Veronika Sanin, Karin Schinke, Simon Schneider, Susanne Sara Schreiber, Friederike Schürmann, Katrin Schweneker, Daniel Sinnecker, Silvia Spörl, Alexander Steger, Ruth Thalmann, Teresa Trenkwalder, Romy Ubrich, Teresa Vitadello, Johannes von Burstin, Gesa von Olshausen, Moritz von Scheidt, Severin Weigand, Florian Weis, Stefanie Weiss (Jilg), Fritz Wimbauer, Isabel Wustrow Study Nurses: Christine Berke, Marianne Eichinger, Heike Fengler, Christoph Gerlach, Ruth Larbre, Conny Plischke, Dagmar Reitberger, Lisa Scheler, Victoria Zillmann Ulm University Hospital, Cardiology Sinisa Markovic (PI, JAN 2019), Jochen Wöhrle (PI, JUN/2014-DEC/2018), Wolfgang Rottbauer (Sub-PI, JAN 2019), Sinisa Markovic (Sub-PI, JUN/2014-DEC/2018) Investigators: Belal Awad, Michael Baumhardt, Peter Bernhardt, Kathrin Blödt, Christoph Bönner, Dominik Buckert, Maciej Cieslik, Tillmann Dahme, Sergiu Dragomir, Nils Dyckmanns, Lukas Gleirscher, Birgid Gonska, Mustafa Gülap, Paul Hartveg, Katrin Herrmann, Barbara Hübers, Armin Imhof, Mirjam Keßler, Christine Kugler, Martin Kullik, Markus Kunze, Angelika Madar, Elnura Mammadova, Christiane Michel, Johannes Mörike, Nicoleta Nita, Rimma Paliskyte, Ursula Paoli, Michael Radermacher, Manuel Rattka, Christoph Rodewald, Dominik Scharnbeck, Meike Schivelbein, Leonhard Schneider, Julia Seeger, Stefan Thamasett, Stephan Tilman, Daniel Walcher, Karolina Weinmann Study Nurses: Marianne Holl, Katharina Kraus, Alexandra Maß, Elif Sacma, Julia Schajti- Gouda, Ulrike Schnee, Olga Smirnova, Anastasia Winter Heart Center Bad Segeberg Gert Richardt (PI), Ralph Tölg (Sub-PI) Investigators: Mohamed Abdel-Wahab, Abdelhakim Allali, Suzanne de Waha, Mohamed El Mawardy, Volker Geist, Ken Gordian, Constanze Merten, Bettina Schwarz, Yazdan Seivani, Björn Stöcker, Dmitry Sulimov Page 3 / 33

5 Study Nurses: Monika Bahnsen-Maass, Friederike Geyer, Ellen Kabel, Kirsten Kassner, Wiebke Mohr-Tödt, Susanne Sachse, Daniela Schürmann-Kuchenbrandt Heart Center, Campus Kerckhoff of Justus-Liebig-University, Giessen Christoph Liebetrau (PI, DEC/2015), Helge Möllmann (PI, MAY/2014-DEC/2015), Christian Hamm (Sub-PI, MAY/2014) Investigators: Johannes Blumenstein, Ulrich Fischer-Rasokat, Luise Gaede, Moritz Haas, Roland Klingenberg, Thore Körschgen, Christian Maikowski, Andreas Rolf, Claudia Walther, Maren Weferling, Kim Won-Keun Study Nurses: Mirabela Cojocaru, Rita Michel, Yvonne Peter, Christina Reuschling, Heike Strohschnitter (Wagner) Helios Amper-Klinikum Dachau, Cardiology & Pneumology, Dachau Bernhard Witzenbichler (PI), Hedda von zur Mühlen (Sub-PI, NOV/2015), Martin Ruß (Sub- PI, OCT/2014-NOV/2015) Investigators: Martin Desaga Study Nurses: Marion Sengewald, Marlene Swoboda University Clinic Mannheim, Cardiology Ibrahim Akin (PI), Michael Behnes (Sub-PI) Investigators: Uzair Ansari, Stefan Baumann, Tobias Becher, Christina Dösch, Christian Fastner, Aydin Huseynov, Ralf Lehmann, David Manuel Leistner, Dirk Loßnitzer, Benedikt Münz Study Nurses: Heike Dietz, Stefanie Dorn, Claudia Föllinger, Ursula Hoffmann, Brigitte Kircher, Tamara Lacina, Regine Muczenski-Luz Klinikum Landkreis Erding, Cardiology Lorenz Bott-Flügel (PI), Nader Joghetaei (Sub-PI) Investigators: Katrin Huber Study Nurses: Yvonne Anders, Sonja Panhofer, Anja Zipfel Page 4 / 33

6 Department of Internal Medicine II, University Medical Center Regensburg Marcus Fischer (PI), Andrea Bäßler (Sub-PI) Investigators: Stefan Buckner, Dierk Endemann, Sabine Fenk, Carsten Jungbauer, Christine Meindl, Christian Schach, Stefan Stadler, Christina Strack, Bernhard Unsöld Study Nurses: Erika Jäger, Esther Kellner, Ingrid Lugauer, Nina Riedlbauer Department of Cardiology, Charité - University Medicine Berlin Ulf Landmesser (PI), David Manuel Leistner (Sub-PI) Investigators: Georg Fröhlich, Christian Michael Gross, Nadija Güc, Andrea Heuberger, Alexander Lauten, Hans-Christian Mochmann, Wolfgang Poller, Ursula Rauch-Kröhnert, Susanne Rutschow, Anne-Sophie Schatz, Vera Schneider, Carsten Skurk, Barbara Elisabeth Stähli, Lisa Steinbeck Study Nurses: Clara Frick, Katja Hubert, Julia Jordan, Anne-Christin Krämer, Stefanie Kühn, Derya Oezcelik, Estefania Roldan Ruiz University Clinic Heidelberg, Cardiology Hugo Albert Katus (PI), Evangelos Giannitsis (Sub-PI) Investigators: Safaa Abudawoud, Ioana Barb, Moritz Biener, Fabrice Darche, Vitali Koch, Matthias Müller, Mehrshad Vafaie Study Nurses: Heidi Deigentasch, Ruth Fischer, Melanie Hütter (Magin), Sascha Maas, Dana Meissner, Elisabeth Mertz, Sibylle Stegmaier Klinik der Universität München, Ludwig Maximilians University, Cardiology, Munich Ralph Hein-Rothweiler (PI, MAR/2019), Dirk Sibbing (PI, JUN/2017-MAR/2019), Julinda Mehilli (Sub-PI, JUN/2017) Investigators: Moritz Baquet, Axel Bauer, Johannes Beil, Johannes Brado, Luisa Freyer, Felix Grabher, Ulrich Grabmaier, Wolfgang Hamm, David Jochheim, Alexander Khandoga, Danny Kupka, Anja Loew, Cynthia Marisch, Michael Mehr, Benjamin Neumann, Martin Orban, Joachim Pircher, Daniel Puhr-Westerheide, Lisa Riesinger, Konstantinos Rizas, Samira Saraj, Jan Schenzle, Clemens Scherer, Johannes Schier, Julius Steffen, Anna Katharina Strüven, Claudia Summo, Raffael Thaler, Manuela Thienel, Nikolay Vdovin, Ludwig Weckbach, Tobias Weinberger, Magda Zadrozny Study Nurse: Janine Vogt Page 5 / 33

7 Helios University Hospital, University of Witten/Herdecke, Department of Cardiology, Wuppertal Melchior Seyfarth (PI), Marc Vorpahl (Sub-PI) Investigators: Till Köhler, Ina Nover, Jacek Szymanski, Klaus Tiroch Study Nurses: David Calvo Sanchez, Sarah Christiani, Bärbel Schanze-Krauskopf, Mareike Schink, Elisabeth Schmidt, Petra Thürmann Schön Klinik Starnberger See, Berg Jürgen Pache (PI), Katharina Hoppe (Sub-PI) Investigators: Christiane Drescher, Roberto Emmer, Daniel Franke, Nicolas Graf, Judit Halmos, Tim Humboldt, Clemens Jilek, Christoph Kempf, Tanja Isabelle Klotz (Sippel), Beatrix Kocso, Julia Kolb, Susanne Metzger, Markus Nies, Aurel Rambeck, Leonie Siering, Anja Wodke, Falko Zink Study Nurses: Lisa Abenthum, Katharina Lang, Dominique Stieber Städtisches Klinikum München GmbH - Klinikum Neuperlach, Cardiology and Pneumology, Munich Harald Mudra (PI), Manuela Segerer (Sub-PI) Investigators: Jaqueline Fiedler, Ralph Hein-Rothweiler, Martin Hug, Alexander Illmann, Malte Müller, Thomas Raeder, Stephan Staubach, Laura Wehweck Study Nurses: Petra Setzer, Anamaria Stote Universitätsmedizin der Johannes Gutenberg-Universität Mainz, Cardiology, Mainz Tommaso Gori (PI), Thomas Münzel (Sub-PI) Investigators: Sebastian Hollmann, Dudu Kutlu, Bettina Ruff Study Nurses: Julia Gadinger, Sophie Pillath, Sarah Rohleder, Ilka Walther Universitätsmedizin Göttingen, Heart Center, Göttingen Claudius Jacobshagen (PI), Tim Seidler (Sub-PI SEP/2015), Samuel Sossalla (Sub-PI, NOV/2014-SEP/2015) Investigators: Bo Eric Beuthner, Frauke Czepluch, Eva Rasenack, Radi Topci, Annabelle Wolk Page 6 / 33

8 Study Nurses: Swetlana Hartmann, Jennifer Heinemann, Anja Hernandez, Nadine Heydrich, Sandra Morik, Kristina Schröder Klinikum Traunstein, Cardiology, Traunstein Werner Moshage (PI), Markus Barth (Sub-PI) Investigators: Thomas Bunse, Alexander Galland, Florian Krahmer Städtisches Klinikum Karlsruhe, Cardiology and Angiology, Karlsruhe Philipp Grotherr (PI), Klaus Böser (Sub-PI) Investigators: Marius Hornung Klinikum Lippe-Detmold, Cardiology and Angiology, Lippe Ulrich Tebbe (PI), Dirk Härtel (Sub-PI) Investigators: Ralf Felgendreher Study Nurses: Marion Denart, Melanie Kriete Page 7 / 33

9 Country: Italy Ospedale Fabrizio Spaziani, Cardiology, Frosinone Maurizio Menichelli (PI) Investigators: Francesco Bellato, Eva Bergamini, Vittorio Bernardi, Duino Boncompagni, Luigi Carbonardi, Marco Cesareo, Stefania Cherubini, Domenico Ciuffetta, Daniele del Vecchio, Giancarlo di Ruzza, Leonardo Genova, Giuseppe Mochi, Pasquale Mollo, Vincenzo Paniccia, Fabio Quanandri, Alessandro Russo, Massimo Savona, Vanessa Venturelli, Cristina Volponi Study Nurses: Maria Ceccani, Barbara Paniccia Careggi University Hospital Firenze, Florence David Antoniucci (PI) Investigators: Angela Migliorini, Guido Parodi, Renato Valenti Page 8 / 33

10 Steering Committee Adnan Kastrati (Chair) Deutsches Herzzentrum München Klinik an der Technischen Universität München Lazarettstr. 36, Munich, Germany Stefanie Schüpke (Schulz) (Coordinating Investigator) Deutsches Herzzentrum München Klinik an der Technischen Universität München Lazarettstr. 36, Munich, Germany Dominick J. Angiolillo University of Florida College of Medicine-Jacksonville Division of Cardiology 655 West 8th Street, Jacksonville, FL 32209, USA David Antoniucci Careggi Hospital, Division of Cardiology Viale Morgagni 85, Firenze, Italy Christian Hamm Kerckhoff-Klinik GmbH Herz-, Thorax- und Rheumazentrum Benekestr. 2-8, Bad Nauheim, Germany Karl-Ludwig Laugwitz 1. Medizinische Klinik und Poliklinik Klinikum rechts der Isar Ismaninger Str. 22, Munich, Germany Franz-Josef Neumann Klinik für Kardiologie und Angiologie II, Universitäts-Herzzentrum Freiburg Bad Krozingen Südring 15, Bad Krozingen, Germany Gert Richardt Segeberger Kliniken GmbH, Klinik für Kardiologie und Angiologie Am Kurpark 1, Bad Segeberg, Germany Helmut Schühlen Vivantes Auguste-Viktoria-Klinikum Rubensstr. 125, Berlin, Germany Heribert Schunkert Deutsches Herzzentrum München Klinik an der Technischen Universität München Lazarettstr. 36, Munich, Germany Page 9 / 33

11 Event Adjudication Committee Klaus Tiroch (Chair) Herz-Zentrum Bodensee Luisenstr. 9A, Konstanz, Germany Clemens Jilek Klinik für Kardiologie und Internistische Intensivmedizin Peter Osypka Herzzentrum Am Isarkanal 36, Munich, Germany Dritan Keta Bezirkskrankenhaus Lienz Emmanuel von Hibler Str. 5, 9900 Lienz, Austria Annunziata Nusca Campus Bio-Medico University of Rome, Department of Cardiovascular Sciences Via Alvaro del Portillo 200, Rome, Italy Stefan Paul Praxis NY Höfe, Praxis für Innere Medizin und Kardiologie Nymphenburger Str. 10d, Munich, Germany Nikolaus Sarafoff kardiologie pneumologie brienner 46 Brienner Str. 46, Munich, Germany Christian Volmer Kardiologische Praxis im Tal Tal 21, Munich, Germany Data Safety Monitoring Board Albert Schömig (Chair) Praxis NY Höfe, Praxis für Innere Medizin und Kardiologie Nymphenburger Str. 10d, Munich, Germany Franz Hofmann Institut für Pharmakologie und Toxikologie der TU München Biedersteiner Str. 29, Munich, Germany Kurt Ulm (Statistician) Klinikum rechts der Isar Institut für Medizinische Informatik, Statistik und Epidemiologie, TU München Ismaninger Str. 22, Munich, Germany Page 10 / 33

12 2. Coordinating ISAResearch Center Deutsches Herzzentrum München, Munich Adnan Kastrati (Chairman), Stefanie Schüpke (Schulz) (Coordinating Investigator), Tanja Morath (Deputy Coordinating Investigator), Katharina Mayer, Isabell Bernlochner, Juliane Jaitner Project Management Marion Janisch, Barbara v. Merzljak, Deborah-Ann Schuster Study Coordination/Study Assistant Elisabeth Strauss, Judith Ruf Data Management Anja Münnich, Nonglag Rifatov, Jayshree Vogel, Oliver Krueger, Antonia Feuchtenberger, Johannes Koloczek, Regina Neujahr, Anke Luttert, Elisabeth Olliges, Andi Rroku, Daniela Schemmer, Michael Valeskini SAE Management Marion Janisch, Tatjana Bruch, Raphaela Hilz (Lohaus), Senta Gewalt, Anke Wasmund, Anna Lena Lahmann, Clarissa Lanig, Tanja Morath, Sara Ates, Julia Birkmeier, Desard Hashorva, Katrin Anette Fiedler, Angela Finzel, Vivien Kujath, Andrea Mecklenburg, Silvia Müller, Traian Popescu, Franziska Prömm, Amke Stuke Monitoring Barbara Rüssmann (Lead Monitor), Stefanie Brunner, Annika Wisnowsky, Massimo Duranti, Julia Wörner, Johannes Boehm, Sonja Meierhöfer, Julia Müller (Weigl), Silvia Müller, Jana Reins, Alexandra Schön, Mechthild Sendhoff Page 11 / 33

13 3. Figures Figure S1. One-Year Incidences and Hazard Ratios of the Primary End Point of Death, Myocardial Infarction, or Stroke in Pre-specified Subgroups CABG: coronary-artery bypass grafting; NSTEMI: non-st-segment elevation myocardial infarction; PCI: percutaneous coronary intervention; STEMI: ST-segment elevation myocardial infarction. Page 12 / 33

14 Percentages are Kaplan-Meier estimates. Hazard Ratios associated with the use of ticagrelor, as compared with prasugrel, are shown with their 95% confidence intervals (CI). Page 13 / 33

15 4. Tables Table S1. Angiographic Characteristics Characteristic Ticagrelor (N = 2003) Prasugrel (N = 2001) Access site femoral no. (%) 1245/2003 (62.2) 1260/2001 (63.0) radial no. (%) 748/2003 (37.3) 731/2001 (36.5) other no. (%) 10/2003 (0.5) 10/2001 (0.5) No. of diseased coronary vessels No obstructive CAD no. (%) 170/2003 (8.5) 164/2001 (8.2) One vessel no. (%) 601/2003 (30.0) 582/2001 (29.1) Two vessels no. (%) 521/2003 (26.0) 555/2001 (27.7) Three vessels no. (%) 711/2003 (35.5) 700/2001 (35.0) Left ventricular ejection fraction % 51.6 ± ± 11.2 Plus-minus values are means ± standard deviation, angiographic data are not available for 14 patients: four patients withdrew consent before angiography and ten patients did not undergo coronary angiography, left ventricular ejection fraction was not available in 211 patients CAD: coronary artery disease Page 14 / 33

16 Table S2. Procedural Characteristics Characteristic Ticagrelor (N = 1676) Prasugrel (N = 1701) More than 1 lesion treated 569/1676 (33.9) 604/1701 (35.5) Target vessel Left main coronary artery no. (%) 36/1676 (2.2) 38/1701 (2.2) Left anterior descending coronary artery no. (%) 746/1676 (44.5) 718/1701 (42.2) Left circumflex coronary artery no. (%) 346/1676 (20.6) 345/1701 (20.3) Right coronary artery no. (%) 520/1676 (31.0) 569/1701 (33.5) Bypass graft no. (%) 28/1676 (1.7) 31/1701 (1.8) Complex lesion (type B2/C) no. (%) 979/1676 (58.4) 1008/1701 (59.3) Thrombolysis in Myocardial Infarction flow grade before the intervention 0 no. (%) 592/1676 (35.3) 584/1701 (34.3) 1 no. (%) 127/1676 (7.6) 155/1701 (9.1) 2 no. (%) 361/1676 (21.5) 386/1701 (22.7) 3 no. (%) 596/1676 (35.6) 576/1701 (33.9) Thrombolysis in Myocardial Infarction flow grade after the intervention 0 no. (%) 17/1676 (1.0) 16/1701 (0.9) 1 no. (%) 9/1676 (0.5) 7/1701 (0.4) 2 no. (%) 50/1676 (3.0) 37/1701 (2.2) Page 15 / 33

17 3 no. (%) 1600/1676 (95.5) 1641/1701 (96.5) Type of intervention Stent implantation Drug-eluting stent no. (%) 1497/1676 (89.3) 1543/1701 (90.7) Bare-metal stent no. (%) 4/1676 (0.2) 8/1701 (0.5) Bioresorbable vascular scaffold no. (%) 99/1676 (5.9) 96/1701 (5.6) Drug-eluting balloon no. (%) 36/1676 (2.2) 27/1701 (1.6) Plain balloon angioplasty no. (%) 57/1676 (3.4) 45/1701 (2.7) Maximal stent diameter mm 3.2 ± ± 0.5 Total stented length mm 30.7 ± ± 17.0 Successful PCI no. (%) 1640/1676 (97.9) 1662/1701 (97.7) Periprocedural antithrombotic medication Aspirin no. (%) 1503/1676 (89.7) 1532/1701 (90.1) Unfractionated heparin no. (%) 1581/1676 (94.3) 1596/1701 (93.8) Low molecular weight heparin no. (%) 74/1676 (4.4) 65/1701 (3.8) Bivalirudin no. (%) 125/1676 (7.5) 141/1701 (8.3) GPIIb/IIIa inhibitor no. (%) 219/1676 (13.1) 198/1701 (11.6) Plus-minus values are means ± standard deviation, maximal stent diameter and total stented length were not available in 1 patient, respectively. GPIIb/IIIa inhibitor: glycoproteiniib/iiia inhibitor, PCI: percutaneous coronary intervention Page 16 / 33

18 Table S3. Diagnosis and Drug Therapy at Discharge Characteristics Ticagrelor (N = 2012) Prasugrel (N = 2006) Final diagnosis of acute coronary syndrome no. (%)* 1830/2006 (91.2) 1813/2004 (90.5) unstable angina 189/1830 (10.3) 173/1813 (9.5) Non-ST-segment elevation MI 834/1830 (45.6) 827/1813 (45.6) ST-segment elevation MI 807/1830 (44.1) 813/1813 (44.8) Therapy at discharge no. (%) Aspirin 1866/1975 (94.5) 1878/1978 (94.9) Ticagrelor 1602/1975 (81.1) 14/1978 (0.7) Prasugrel 21/1975 (1.1) 1596/1978 (80.7) Clopidogrel 90/1975 (4.6) 117/1978 (5.9) Oral anticoagulant drugs 82/1975 (4.2) 100/1978 (5.1) Betablocker 1641/1975 (83.1) 1645/1978 (83.2) ACE inhibitor/arb 1659/1975 (84.0) 1690/1978 (85.4) Statin 1810/1975 (91.6) 1831/1978 (92.6) * not available in 8 patients who withdrew consent before discharge, shown for patients discharged alive, not available in 8 patients who withdrew consent ACE: angiotensin converting enzyme, ARB: angiotensin receptor blocker, MI: myocardial infarction Page 17 / 33

19 Table S4. Antithrombotic Medication After Discontinuation of Study Drug During Follow-up Characteristic Ticagrelor (N = 243) Prasugrel (N = 199) Ticagrelor no. (%) 0 (0.0) 14 (7.0) Prasugrel no. (%) 35 (14.4) 0 (0.0) Clopidogrel no. (%) 119 (49.0) 106 (53.3) Oral anticoagulation no. (%) 40 (16.5) 44 (22.1) None of the aforementioned medication 78 (32.1) 64 (32.2) We analyzed the composite end point of all-cause death, myocardial infarction, or stroke among patients discharged on study drug (1602 patients in the ticagrelor group and 1596 in the prasugrel group) from discharge to the time of discontinuation or end of follow-up ("on treatment" analysis). There were 163 events, 92 in the ticagrelor group and 71 in the prasugrel group (hazard ratio 1.34 [95% confidence interval ]). In a similar analysis, there were 107 myocardial infarctions, 64 in the ticagrelor group and 43 in the prasugrel group (hazard ratio 1.54 [95% confidence interval ]). Page 18 / 33

20 Table S5. Base-Line Characteristics of Patients with Incomplete vs Complete One-Year Follow-up Incomplete Complete Characteristic Follow-up Follow-up P value (N = 90) (N = 3928) Age years 67 ± ± Women no. (%) 23 (25.6) 933 (23.8) 0.79 Diabetes no. (%) 22 (24.4) 870 (22.2) 0.70 insulin-treated no. (%) 5 (5.6) 275 (7.0) 0.75 Current smoker no. (%) 27 (30.3) 1322 (33.8) 0.57 Arterial hypertension no. (%) 70 (77.8) 2746 (70.0) 0.14 Hypercholesterolemia no. (%) 54 (60.0) 2287 (58.3) 0.84 Prior myocardial infarction no. (%) 18 (20.0) 613 (15.6) 0.33 Prior percutaneous coronary intervention no. 28 (31.1) 888 (22.6) 0.08 (%) Prior aortocoronary bypass surgery no. (%) 4 (4.4) 241 (6.1) 0.66 Cardiogenic shock no. (%) 1 (1.1) 64 (1.6) >0.99 Blood pressure systolic mmhg 145 ± ± diastolic mmhg 82 ± ± Heart rate beats/min 74 ± ± Body mass index kg/m² 27.2 ± ± Weight < 60 kg 5 (5.7) 197 (5.1) 0.80 Creatinine µmol/l 87 ± ± Diagnosis at admission 018 Unstable angina no. (%) 15 (16.7) 495 (12.6) Page 19 / 33

21 NSTEMI no. (%) 46 (51.1) 1809 (46.1) STEMI no. (%) 29 (32.2) 1624 (41.3) Coronary angiography no. (%) 86 (95.6) 3918 (99.7) <0.001 Treatment strategy no. (%) 0.15 PCI 67 (77.9) 3310 (84.3) CABG 1 (1.2) 82 (2.1) conservative 18 (20.1) 535 (13.6) Plus-minus values are means ± standard deviation CABG: coronary artery bypass grafting; NSTEMI: Non-ST-segment elevation myocardial infarction, PCI: percutaneous coronary intervention, STEMI: ST-segment elevation myocardial infarction Page 20 / 33

22 5. Inclusion and Exclusion Criteria Inclusion criteria Hospitalization for an acute coronary syndrome (unstable angina pectoris, non-stsegment elevation myocardial infarction, or ST-segment elevation myocardial infarction) with planned invasive strategy ST-segment elevation myocardial infarction Chest discomfort suggestive of cardiac ischemia 20 minutes at rest, within 24 h prior to randomization with 1 of the following ECG features: - ST-segment elevation 1 mm in 2 contiguous ECG leads or - new or presumably new left bundle branch block (LBBB) Non-ST-segment elevation acute coronary syndrome (unstable angina or non-st-segment elevation myocardial infarction) Chest discomfort suggestive of cardiac ischemia for 10 minutes at rest within 48 h prior to randomization + 1 of the following criteria: - ST-segment depression 1 mm in 1 or 2 contiguous ECG leads or - Troponin T or I or CK-MB greater than the upper limit of normal or - 2 of the following clinical criteria: Age 60 years 3 risk factors for coronary artery disease (arterial hypertension, hypercholesterolemia, family history, diabetes mellitus, current smoker) Diabetes mellitus Page 21 / 33

23 Aspirin use in the past 7 days Severe angina ( 2 episodes within the last 24 hours) Chronic renal dysfunction Prior MI or CABG Known CAD with 50% stenosis in 2 vessels Carotid stenosis 50% or cerebral revascularization Peripheral artery disease age 18 years Exclusion criteria intolerance of or allergy to ticagrelor or prasugrel history of any stroke, transient ischemic attack or intracranial bleeding known intracranial neoplasm, intracranial arteriovenous malformation or intracranial aneurysm active bleeding, clinical findings, that in the judgement of the investigator are associated with an increased risk of bleeding fibrin-specific fibrinolytic therapy less than 24 h before randomization, non-fibrinspecific fibrinolytic therapy less than 48 h before randomization known platelet count < /μL at the time of screening Page 22 / 33

24 known anemia (hemoglobin < 10 g/dl) at the time of screening oral anticoagulation that cannot be safely discontinued for the duration of the study INR known to be greater than 1.5 at the time of screening chronic renal insufficiency requiring dialysis moderate or severe hepatic dysfunction (Child Pugh B or C) increased risk of bradycardia events (Sick Sinus, AV block grade II or III, bradycardia-induced syncope) index event is an acute complication (< 30 days) of PCI concomitant medical illness that in the opinion of the investigator is associated with a life expectancy < 1 year concomitant oral or i.v. therapy with strong CYP3A inhibitors (e.g. ketoconazole, itraconazole, voriconazole, telithromycin, clarithromycin, nefazodone, ritonavir, saquinavir, nelfinavir, indinavir, atazanavir, grapefruit juice >1 L/d), CYP3A substrates with narrow therapeutic indices (e.g. cyclosporine, quinidine), or strong CYP3A inducers (e.g. rifampin/rifampicin, phenytoin, carbamazepine, dexamethason, phenobarbital) that cannot be safely discontinued 1 doses of ticagrelor or prasugrel within 5 days before randomization no written informed consent participation in another investigational drug study previous enrolment in this study Page 23 / 33

25 for women of childbearing potential no negative pregnancy test and no agree to use a reliable method of birth control during the study pregnancy, giving birth within the last 90 days, or lactation inability to cooperate with protocol requirements Page 24 / 33

26 6. End point definitions Death 1 The primary end point includes death from any cause. In addition, the cause of death will be adjudicated. If autopsy has been performed autopsy reports should be solicited for determination of cause of death. Cardiac death Any death due to proximate cardiac cause (e.g. myocardial infarction, low-output failure, fatal arrhythmia), unwitnessed death and death of unknown cause, and all procedure-related deaths, including those related to concomitant treatment, will be classified as cardiac death. Vascular death Death caused by noncoronary vascular causes, such as cerebrovascular disease, pulmonary embolism, ruptured aortic aneurysm, dissecting aneurysm, or other vascular diseases. Noncardiovascular death Any death not covered by the above definitions, such as death caused by infection, malignancy, sepsis, pulmonary causes, accident, suicide, or trauma. All deaths are considered cardiac unless an unequivocal noncardiac cause can be established. Specifically, any unexpected death even in patients with coexisting potentially fatal noncardiac disease (e.g. cancer, infection) should be classified as cardiac. Myocardial infarction The definition of myocardial infarction used in this trial is adapted from the Third Universal Definition of Myocardial Infarction. 2 Cardiac troponin will be used as the preferred biomarker. CK-MB (and CK) values will be assessed concurrently and used in the case that troponin values are not available. Page 25 / 33

27 1. Spontaneous myocardial infarction, not related to PCI or CABG Detection of a rise and/or fall in cardiac biomarkers (preferebly cardiac troponin) with at least one value above the 99th percentile upper reference limit (URL) and with at least one of the following - symptoms of ischemia - development of pathological Q waves in the ECG - new or presumed new ST-segment - T-wave changes (ST-T changes) or new left bundle branch block - imaging evidence of new loss of viable myocardium or new regional wall motion abnormality 2. Myocardial infarction after randomization and before PCI Recurrent symptoms of cardiac ischemia or hemodynamic instability plus one of the following criteria - new or presumed new ST-segment elevation or new left bundle branch block distinct from the last ECG or - in patients with normal biomarkers and not presenting with ST-segment elevation MI on admission: detection of a rise and/or fall in cardiac biomarkers (preferably cardiac troponin) with at least one value above the 99th percentile upper reference limit (URL) - if the baseline Troponin values are elevated and are stable or falling, then a rise of >20% is required - development of new pathological Q waves in the ECG distinct from the coronary territory identified on admission - imaging evidence of new loss of viable myocardium or new regional wall motion abnormality 3. PCI-related myocardial infarction (within 48 h after PCI) Cardiac enzymes (Troponin T or I, CK and CK-MB) will be determined on admission, 4-6 hours after admission (before angiography, in all patients with non-urgent PCI) and from blood drawn from the arterial sheath in the cath lab immediately after sheath insertion and before PCI. Biomarker course will be used for redefinition of baseline status in patients with NSTE-ACS, i.e. to differentiate unstable angina pectoris from NSTEMI and to better describe biomarker course in NSTEMI patients. Page 26 / 33

28 Based on the 2 sets of biomarkers the baseline status will be redefined: - If biomarkers on admission have been normal (initial diagnosis of unstable angina) and biomarkers are rising > 99th percentile URL in the second sample (before catherization or from the arterial sheath) without recurrent symptoms of ischemia the initial diagnosis of unstable angina is revised to NSTEMI on admission. - If biomarkers on admission have been elevated (diagnosis of NSTEMI) then it will be documented whether biomarker values are stable, rising or falling Unstable angina at baseline In patients undergoing PCI with normal (<99th percentile URL) baseline Troponin concentrations, elevations of Troponin >5 x 99th percentile URL occurring within 48 h of the procedure plus either - evidence of prolonged ischemia (>20 min) as demonstrated by prolonged chest pain or - ischaemic ST-changes or new pathological Q waves, or - angiographic evidence of a flow limiting complication, such as of loss of patency of a side branch, persistent slow-flow or no-reflow, embolization, or - imaging evidence of new loss of viable myocardium or new regional wall motion abnormality will be defined as PCI-related MI. In patients with recent symptoms (<6 h) before admission, no second blood sample before catherization, a short interval from biomarker assessment on admission and in the cath lab and normal values in both samples it will be challenging to differentiate an ongoing myocardial infarction from post-pci myocardial infarction. In this case the diagnosis of myocardial infarction requires criteria as defined in section 3.3 for patients with rising biomarkers. 3.2 NSTEMI with documented stable or falling biomarkers If the baseline Troponin values are elevated and are stable or falling, then a rise of >20% is required for the diagnosis of reinfarction. In addition, either - symptoms suggestive of myocardial ischemia or hemodynamic instability, or - new ischemic ECG changes or new LBBB, or Page 27 / 33

29 - angiographic loss of patency of a major coronary artery or a side branch or persistent slow- or no-flow or embolization, or - imaging demonstration of new loss of viable myocardium or new regional wall motion abnormality are required NSTEMI with rising biomarkers or STEMI - new symptoms suggestive of myocardial ischemia or hemodynamic instability plus - new ischemic ECG changes or new LBBB plus - angiographic loss of patency of a major coronary artery or a side branch or persistent slow- or no-flow or embolization 4. Myocardial infarction related to CABG Myocardial infarction associated with CABG is defined by elevation of cardiac biomarker values >10 x 99th percentile URL in patients with normal baseline Troponin values (<99th percentile URL) in addition to either - new pathological Q waves or new LBBB, or - angiographic documented new graft or new native coronary artery occlusion, or - imaging evidence of new loss of viable myocardium or new regional wall motion abnormality 5. Criteria for prior myocardial infarction - pathological Q waves with or without symptoms in the absence of non-ischemic causes - imaging evidence of a region of loss of viable myocardium that is thinned and fails to contract, in the absence of a non-ischemic cause - pathological findings of a prior MI - medical recording that clearly states that the patient had a MI Based on the Third universal definition, myocardial infarction will be classified into various types: Type 1 Spontaneous myocardial infarction Spontaneous myocardial infarction related to atherosclerotic plaque rupture, ulceration, fissuring, erosion, or dissection with resulting intraluminal thrombus in one or Page 28 / 33

30 more of the coronary arteries leading to decreased myocardial blood flow or distal platelet emboli with ensuing myocyte necrosis. The patient may have underlying severe CAD but on occasion non-obstructive or no CAD. Type 2 Myocardial infarction secondary to an ischemic imbalance In instances of myocardial injury with necrosis where a condition other than CAD contributes to an imbalance between myocardial oxygen supply and/or demand, e.g. coronary endothelial dysfunction, coronary artery spasm, coronary embolism, tachy-/brady-arrhythmias, anemia, respiratory failure, hypotension, and hypertension with or without left ventricular hypertrophy. Type 3 Myocardial infarction resulting in death when biomarker values are unavailable Myocardial infarction resulting in death when biomarker values are unavailable. Cardiac death with symptoms suggestive of myocardial ischemia and presumed new ischemic ECG changes or new LBBB, but death occurring before blood samples could be obtained, before cardiac biomarker could rise, or in rare cases cardiac biomarkers were not collected. Type 4a Myocardial infarction related to percutaneous coronary intervention (PCI) Myocardial infarction associated with PCI is arbitrarily defined by elevation of ctn values 5 x 99th percentile URL in patients with normal baseline values (< 99th percentile URL) or a rise of ctn values 20% if the baseline values are elevated and are stable or falling. In addition, either (i) symptoms suggestive of myocardial ischemia, or (ii) new ischemic ECG changes or new LBBB, or (iii) angiographic loss of patency of a major coronary artery or a side branch or persistent slow- or no-flow or embolization, or (iv) imaging demonstration of new loss of viable myocardium or new regional wall motion abnormality are required. Page 29 / 33

31 Type 4b Myocardial infarction related to stent thrombosis Myocardial infarction associated with stent thrombosis is detected by coronary angiography or autopsy in the setting of myocardial ischemia and with a rise and/ or fall of cardiac biomarkers values with at least one value above the 99th percentile URL. Type 5 Myocardial infarction related to coronary artery bypass grafting (CABG) Myocardial infarction associated with CABG is arbitrarily defined by elevation of cardiac biomarker values 10 x 99th percentile URL in patients with normal baseline ctn values (99th percentile URL). In addition, either (i) new pathological Q waves or new LBBB, or (ii) angiographic documented new graft or new native coronary artery occlusion, or (iii) imaging evidence of new loss of viable myocardium or new regional wall motion abnormality. Stroke Stroke is defined as the new onset of focal or global neurological deficit caused by ischemia or hemorrhage within or around the brain and lasting for more than 24 hours or leading to death. The diagnosis of stroke requires confirmation by CT, MRI or autopsy. Ethiology: - intracranial hemorrhage will be diagnosed by appropriate brain imaging (e.g. CT or MRI) that shows the presence of an acute blood mass - ischemic or bland infarction will be diagnosed by appropriate imaging which shows the presence of one or more of the following: hypodensity, edema, midline shift, or ventricular effacement without evidence of hemorrhage - hemorrhagic conversion of an ischemic infarction will be diagnosed by appropriate imaging that shows an ischemic infarction with localized petechial or confluent bleeding into necrotic tissue Page 30 / 33

32 Degree of severity: Non disabling stroke: - If he or she had no sequels or only a minor deficit (with the functional status unchanged). Modified Rankin scale grade of 3 (see below) Disabling stroke: - If at the time of hospital discharge he or she had a moderate deficit (substantial limitation of activity and capabilities) or a severe deficit (inability to live independently or work). Modified Rankin scale grade of 4 (see below) Modified Rankin Scale - Stroke severity assessment scale Scale 0 No symptoms at all Scale 1 No significant disability despite symptoms: able to carry out all usual duties and activities Scale 2 Slight disability: unable to carry out all previous activities but able to look after own affairs without assistance Scale 3 Moderate disability: requiring some help, but able to walk without assistance Scale 4 Moderately severe disability: unable to walk without assistance, and unable to attend to own bodily needs without assistance Scale 5 Severe disability: bedridden incontinent and requiring constant nursing care and attention Scale 6 Death Stent Thrombosis Stent thrombosis will be classified according to the Academic Research Consortium 1 : Definite: Probable: Possible: Presence of an acute coronary syndrome with angiographic or autopsy evidence of thrombus or occlusion. unexplained deaths within 30 days after the procedure or acute myocardial infarction involving the target-vessel territory without angiographic confirmation. all unexplained deaths occurring at least 30 days after the procedure. Early: 0 to 30 days Page 31 / 33

33 Late: 31 to 360 days Very late: > 360 days Bleeding These include all bleeding complications occurring after randomization of the patient. Bleeding localization, amount of hemoglobin drop (if available) and the number of blood units transfused must be recorded in the Case Report Form. Bleeding Academic Research Consortium Definition for Bleeding 3 Type 0: No bleeding Type 1: Bleeding that is not actionable and does not cause the patient to seek unscheduled performance of studies, hospitalization, or treatment by a healthcare professional; may include episodes leading to self-discontinuation of medical therapy by the patient without consulting a healthcare professional Type 2: Any overt, actionable sign of hemorrhage (e.g. more bleeding than would be expected for a clinical circumstance, including bleeding found by imaging alone) that does not fit the criteria for type 3, 4, or 5 but does meet at least one of the following criteria: requiring nonsurgical, medical intervention by a healthcare professional, (2) leading to hospitalization or increased level of care, or (3) prompting evaluation Type 3 Type 3a Overt bleeding plus hemoglobin drop of 3 to < 5 g/dl* (provided hemoglobin drop is related to bleed) Any transfusion with overt bleeding Type 3b Overt bleeding plus hemoglobin drop 5 g/dl* (provided hemoglobin drop is related to bleed) Cardiac tamponade Bleeding requiring surgical intervention for control (excluding dental, nasal, skin or hemorrhoid) Bleeding requiring intravenous vasoactive agents Type 3c Intracranial hemorrhage (does not include microbleeds or hemorrhagic transformation, does include intraspinal) Subcategories confirmed by autopsy or imaging or lumbar puncture Intraocular bleed compromising vision Page 32 / 33

34 Type 4: Type 5: Type 5a Type 5b CABG-related bleeding: Perioperative intracranial bleeding within 48 h Reoperation after closure of sternotomy for the purpose of controlling bleeding Transfusion of 5 U whole blood or packed red blood cells within a 48-h period Chest tube output 2L within a 24-h period Fatal bleeding Probable fatal bleeding; no autopsy or imaging confirmation but clinically suspicious Definite fatal bleeding; overt bleeding or autopsy or imaging confirmation Platelet transfusions should be recorded and reported but are not included in these definitions until further information is obtained about the relationship to outcomes. If a CABG-related bleed is not adjudicated as at least a type 3 severity event, it will be classified as not a bleeding event. If a bleeding event occurs with a clear temporal relationship to CABG (i.e., within a 48-h time frame) but does not meet type 4 severity criteria, it will be classified as not a bleeding event. * Corrected for transfusion (1 U packed red blood cells or 1 U whole blood=1 g/dl hemoglobin). Cell saver products are not counted. 7. References 1. Cutlip DE, Windecker S, Mehran R, et al. Clinical end points in coronary stent trials: a case for standardized definitions. Circulation 2007;115: Thygesen K, Alpert JS, Jaffe AS, et al. Third universal definition of myocardial infarction. Eur Heart J 2012;33: Mehran R, Rao SV, Bhatt DL, et al. Standardized bleeding definitions for cardiovascular clinical trials: a consensus report from the Bleeding Academic Research Consortium. Circulation 2011;123: Page 33 / 33